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Guidelines for treatment of patients with Ebola Virus Diseases are urgently needed

  • Author Footnotes
    1 ProMED Moderator, Parasitic Diseases
    Eskild Petersen
    Footnotes
    1 ProMED Moderator, Parasitic Diseases
    Affiliations
    Editor-in-Chief, International Journal of Infectious Diseases, Professor of Tropical Medicine, Department of Infectious Diseases and Clinical Microbiology, Aarhus University Hospital, Aarhus, Denmark
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  • Author Footnotes
    2 ProMED Moderator for Infectious Diseases, ProMED-FRA (Francophone Africa)
    Boubacar Maiga
    Footnotes
    2 ProMED Moderator for Infectious Diseases, ProMED-FRA (Francophone Africa)
    Affiliations
    Faculty of Medicine and Odonto-Stomatology, University of Sciences, Techniques and, Technology of Bamako (USTTB) of Bamako, Mali
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  • Author Footnotes
    1 ProMED Moderator, Parasitic Diseases
    2 ProMED Moderator for Infectious Diseases, ProMED-FRA (Francophone Africa)
Open AccessPublished:December 03, 2014DOI:https://doi.org/10.1016/j.ijid.2014.12.002
      The Ebola Virus Diseases, EVD, epidemic is still unfolding in West Africa with Guinea, Sierra Leone and Liberia most severely affected. This week it was estimated that there is at least 500 new cases every week and the total number of cases has passed 16,000, but there is probably a substantial underreporting of both cases and fatalities. There are some doubts about the mortality rate, but one recent case series reported a mortality of 72%.
      • Schieffelin J.S.
      • Shaffer J.G.
      • Goba A.
      • Gbakie M.
      • Gire S.K.
      • Colubri A.
      • et al.
      for the KGH Lassa Fever Program, the Viral Hemorrhagic Fever Consortium, and the WHO Clinical Response Team
      Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone.
      The outbreak is unprecedented in magnitude and few would have predicted that such an outbreak was possible. However, it seems clear that it is not due to a more pathogenic version of the Ebola virus and indeed low virus genetic diversity has been observed in person-to-person virus transmission.
      • Carroll S.A.
      • Towner J.S.
      • Tara K.
      • Sealy T.K.
      • McMullan L.K.
      • Khristova M.L.
      • et al.
      for the Viral Special Pathogens Branch and Biotechnology Core Facility Branch
      Molecular Evolution of Viruses of the Family Filoviridae Based on 97 Whole-Genome Sequences.

      Baize S, Pannetier D, Oestereich L, et al. Emergence of Zaire Ebola virus disease in Guinea — preliminary report. N Engl J Med. DOI: 10.1056/NEJMoa1404505.

      Therefore, the current situation is most probable due to the poor status of the health care systems especially in Liberia and Sierra Leone, which has both recently suffered long civil wars, which have left the countries drained for educated health care staff and a dilapidated health infrastructure.
      There is no approved, specific treatment of EVD. Several experimental anti-virals, immune-therapy
      • Qiu X.
      • Wong G.
      • Audet J.
      • Bello A.
      • FernandoL
      • Alimonti J.B.
      • et al.
      Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp.
      and use of hyperimmune plasma from survivors have been proposed, but data from controlled clinical trials are lacking.
      • Yazdanpanah Y.
      • Arribas J.R.
      • Malvy D.
      Treatment of Ebola virus disease.
      After a slow start the international community including many Non Governmental Organizations, NGO's, are managing treatment facilities in West Africa
      But what are these treatment facilities offering?
      Very little data has emerged. One published study reported a mortality of 72% but astonishingly the study contained no information of any treatment.
      • Schieffelin J.S.
      • Shaffer J.G.
      • Goba A.
      • Gbakie M.
      • Gire S.K.
      • Colubri A.
      • et al.
      for the KGH Lassa Fever Program, the Viral Hemorrhagic Fever Consortium, and the WHO Clinical Response Team
      Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone.
      Thus the question remains if the patients included in that study received any treatment at all. These patients were all from Sierra Leone and in contrast, nationals from industrialized countries are evacuated and treated in their home country and survived.
      • Kreuels B.
      • Wichmann D.
      • Emmerich P.
      • Schmidt-Chanasit J.
      • Heer G. de
      • Kluge S.
      • et al.
      A Case of Severe Ebola Virus Infection Complicated by Gram-Negative Septicemia.
      • Lyon G.M.
      • Mehta A.K.
      • Varkey J.B.
      • Brantly K.
      • Plyler L.
      • McElroy A.K.
      • et al.
      for the Emory Serious Communicable Diseases Unit
      Clinical Care of Two Patients with Ebola Virus Disease in the United States.
      In particular, the case evacuated to Germany
      • Kreuels B.
      • Wichmann D.
      • Emmerich P.
      • Schmidt-Chanasit J.
      • Heer G. de
      • Kluge S.
      • et al.
      A Case of Severe Ebola Virus Infection Complicated by Gram-Negative Septicemia.
      show very clearly that the treatment with classical tools used for patients in severe chock (bacterial septicemia, severe malaria) is expected to substantially reduce mortality. The patients received 30 liters of fluid intravenously over the first three days, had paralytic ileus and thus could not take oral fluid, had an fecal output of 14 liters over three days and severe hypokalemia. The same problems were seen in the two patients evacuated to the United States and one of these also had malaria.
      • Lyon G.M.
      • Mehta A.K.
      • Varkey J.B.
      • Brantly K.
      • Plyler L.
      • McElroy A.K.
      • et al.
      for the Emory Serious Communicable Diseases Unit
      Clinical Care of Two Patients with Ebola Virus Disease in the United States.
      Is this a proper level of inpatient care in the Ebola treatment facilities or should we aim higher?
      A mortality of 43% were reported in a case series of 80 patients with EVD from Guinea where 76% of the patients received intravenous fluid even though only 1 titer over 24 hours in average.
      • Bah E.I.
      • Lamah M.-C.
      • Fletcher T.
      • Jacob S.T.
      • Brett-Major D.M.
      • Sall A.A.
      • et al.
      Clinical Presentation of Patients with Ebola Virus Disease in Conakry, Guinea.
      If the difference in mortality between the report from Sierra Leone (72%)
      • Schieffelin J.S.
      • Shaffer J.G.
      • Goba A.
      • Gbakie M.
      • Gire S.K.
      • Colubri A.
      • et al.
      for the KGH Lassa Fever Program, the Viral Hemorrhagic Fever Consortium, and the WHO Clinical Response Team
      Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone.
      and Guinea (43%)
      • Bah E.I.
      • Lamah M.-C.
      • Fletcher T.
      • Jacob S.T.
      • Brett-Major D.M.
      • Sall A.A.
      • et al.
      Clinical Presentation of Patients with Ebola Virus Disease in Conakry, Guinea.
      are due to the use of intravenous fluid and even though one liter intravenous fluid seems very modest in view the need in the three expatriated cases
      • Kreuels B.
      • Wichmann D.
      • Emmerich P.
      • Schmidt-Chanasit J.
      • Heer G. de
      • Kluge S.
      • et al.
      A Case of Severe Ebola Virus Infection Complicated by Gram-Negative Septicemia.
      • Lyon G.M.
      • Mehta A.K.
      • Varkey J.B.
      • Brantly K.
      • Plyler L.
      • McElroy A.K.
      • et al.
      for the Emory Serious Communicable Diseases Unit
      Clinical Care of Two Patients with Ebola Virus Disease in the United States.
      , it seems that intravenous fluid replacement may significantly reduce mortality in the treatment centers perhaps by as much as 50%. This can be done in the conditions prevailing in West Africa using pulse, blood pressure, body weight and urine output as guidance and using simple point-of-care tests for measuring electrolytes, but require intravenous access, abundant fluid for intravenous administration and trained staff.
      It is telling that the NGO's have not published any treatment results and it is unclear if there is any control of treatment outcomes in EVD treatment facilities. Simply notifying confirmed cases and outcomes (fatal or not) and publishing weekly updates broken down to different NGO's would allow quality control and allow adjustment of treatment algorithms adopting procedures identifying the highest survival rates. The difference in mortality between the two published case series
      • Schieffelin J.S.
      • Shaffer J.G.
      • Goba A.
      • Gbakie M.
      • Gire S.K.
      • Colubri A.
      • et al.
      for the KGH Lassa Fever Program, the Viral Hemorrhagic Fever Consortium, and the WHO Clinical Response Team
      Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone.
      • Bah E.I.
      • Lamah M.-C.
      • Fletcher T.
      • Jacob S.T.
      • Brett-Major D.M.
      • Sall A.A.
      • et al.
      Clinical Presentation of Patients with Ebola Virus Disease in Conakry, Guinea.
      indicate that this is urgently needed.
      We must to ensure that treatment is not palliation and that the so-called “Ebola hospitals” are hospitals and not hospices for untreated cases with the sole purpose of isolating cases from the community.
      It is estimated in a study from Liberia, that only 25% of known Ebola patients had been admitted to an Ebola treatment facility as of August 14, 2014.

      Ministry of Health & Social Welfare. Liberia Ebola SitRep no. 91; August 14, 2014. Available at http://www.humanitarianresponse.info/operations/liberia/document/liberia-ebola-sitrep-no-91. Cited in: Matanock A, Arwady MA, Ayscue P, Forrester JD, Gaddis B, Hunter JC, Monroe B, Pillai SK, Reed C, MD5, Schafer IJ, Massaquoi M, Dahn B, Kevin M, Cock KM De. Ebola Virus Disease Cases Among Health Care Workers Not Working in Ebola Treatment Units — Liberia, June–August, 2014. MMWR Morb Mortal Wkly Rep 2014;63:1077-81.

      The reasons for this low number are many, but a key point is probably that the chance of survival in these units does not differ significantly from patients staying at home.
      The national governments in the affected countries does not have the resources nor the manpower to ensure the quality of the care provided by NGO's and others. Thus the World Health Organization or others with the necessary resources should establish a notification system, to ensure that facilities are providing treatment and not only palliation and publish for instance weekly updates of survival figures broken down for each NGO to ensure quality control, transparency and optimization of treatment algorithms.
      The German patient
      • Kreuels B.
      • Wichmann D.
      • Emmerich P.
      • Schmidt-Chanasit J.
      • Heer G. de
      • Kluge S.
      • et al.
      A Case of Severe Ebola Virus Infection Complicated by Gram-Negative Septicemia.
      had septicemia and one of the American patients had malaria.
      • Lyon G.M.
      • Mehta A.K.
      • Varkey J.B.
      • Brantly K.
      • Plyler L.
      • McElroy A.K.
      • et al.
      for the Emory Serious Communicable Diseases Unit
      Clinical Care of Two Patients with Ebola Virus Disease in the United States.
      Both diagnosis can lead to disseminated intravascular coagulation and will thus easily be confused with Ebola. If diagnostics are not available perhaps every patients in this highly endemic malaria area should receive a malaria treatment course and an infusion of a broad spectrum antibiotic, for instance ceftriaxone.
      It is important to know if a patient is HIV positive as a low CD4 T cell count is expected to increase the risk of a fatal outcome, and thus treatment efficacy if at all possible should be stratified according to HIV status.
      It is urgently needed to develop guidelines for treatment of EVD patients and to distinguish treatment from palliation and hospitals from hospices.
      We suggest that the World Health Organization take the leadership and develop guidelines for treatment including:
      • 1.
        Diagnosis of EVD
      • 2.
        Principles for intravenous fluid replacement
      • 3.
        Principles for measurement of electrolyte imbalance
      • 4.
        Principles for correction of electrolyte imbalance
      • 5.
        Diagnosis and treatment of concomitant malaria
      • 6.
        When to administer antibiotics based on suspicion of septicemia
      • 7.
        HIV testing.
      • 8.
        Implement a reporting system for all EVD treatment facilities
      These measures can all be implemented under the field conditions in West Africa, provided the staff are trained in high volume fluid replacement. Participating should be a prerequisite for receiving financial support from governments and receiving permission to manage EVD treatment facilities.
      The staffing of the treatment facilities is a crucial issue and it can be speculated that the NGO's does not have access to physicians and nurses with knowledge and experience in high volume fluid replacement and correction of electrolyte imbalance.
      One solution could be twinning with hospitals in industrialized countries where these hospitals adopt an EVD treatment facility and ensure staffing and training. This of course would need support from the national health authorities. Such a program would ensure effective intravenous fluid replacement therapy were preovided, most probably significantly reduce mortality, ensure confidence in the treatment facilities from the local population and thus increase the use of these facilities (earlier admission and higher proportion of cases treated, isolated and recovered).

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